	Data integrity is an important issue for pharmaceutical manufacturing. 

 spoke with Oliver Wolf, senior product manager at 

, about some of the benefits and challenges of ensuring data integrity using electronic systems.

 What are the primary data integrity risks associated with paper-based systems and with computerized systems? How can these risks be mitigated?

 The primary data integrity risks associated with paper-based systems are data loss, data accuracy, and process integrity. All of these risks can be reduced or even eliminated effectively through computerized systems. In the physical world, complete data loss can occur through something as simple as losing track of a piece of paper or something as calamitous as a fire. Well-designed computer systems will make complete data loss virtually impossible as long as an effective backup and disaster recovery system is in place.

	Data accuracy can be compromised by honest mistakes or willful tampering with data, whether you are working in a paper or an electronic system. Electronic systems can eliminate many common sources of errors by automating data processing steps, such as data transcription and calculations. When it comes to willful falsification, more automation does mean less opportunity for tampering. In practice, however, most electronic systems still rely on humans to some degree. These systems do improve detectability but nonetheless still rely on strong review and approval processes.

	In FDA-regulated environments, recording who reviewed and approved the data is a crucial element. Paper systems can do a decent job in defining the reviewer/approver, but again rely on human review to catch routing errors that an electronic system may eliminate.

	An added risk in electronic records stems from the easy data access these systems afford, which raises the concern that an unauthorized person could access your data. FDA's approach emphasizes that systems need to be designed in a way that such falsification would require the collusion of at least two people. Simply put, while your database administrator may have the ability to alter data without much of a trace, this role does not typically have the motive to do so. Outsiders’ access to your data still obviously is a concern, and implementing sound security procedures is extremely important.

 How can manipulation of electronic records be detected?

 Well-designed electronic systems have mechanisms in place to ensure that data simply cannot be altered through ordinary means by their users when it is not meant to be changed. So, in these systems you would expect that records, once approved, are simply put into read-only mode. In cases where edits are required after the fact, such systems would only allow edits once the record is revised, or at least is bumped back into an ‘in-process’ state. Either mechanism requires personnel to run through an approval process again. This will generate a full record of the changes made and approvals committed.

 Part 11 outlines a number of requirements that FDA-regulated companies must meet in their use of electronic records and signatures. This includes requirements for user passwords, audit trails, and mechanisms that tie an electronic signature to the record it signs. Although this does not mean that it is impossible to change data, for example by gaining direct database access, even a technically proficient person would have trouble updating all records to avoid contradictory data. If data tampering of this level of sophistication is suspected, a good place to start is to compare date and timestamps between activity logs, audit trails, signatures, and the record itself.

 What are the requirements of/best practices for validating a computer system/electronic records?

In FDA-regulated industries, the entity using a computer system is responsible for validation-ensuring the proper functioning of all aspects of the system. Using a risk-based approach to assess high-risk areas of a given system, and then focusing validation testing on those areas, has become acceptable. It has also become acceptable to rely on vendor documentation for testing of the lower-risk areas, especially when the reliability of the documentation has been confirmed through a vendor audit.

	What the high-risk areas of a given system are depends on many factors, including the types of products a company or facility manufactures and what impact the data processed in the system could have on the integrity of these products. System functionality to focus on would certainly include data access and security, electronic signatures, approval processes, and audit trails. 

 What do you see as the most important thing for companies to do or recognize regarding manufacturing data integrity? 

 The most challenging aspect in the implementation of computerized systems in FDA-regulated industries seems to be finding a solid balance between ensuring your risk exposures are mitigated and not stifling your use of innovative systems by being overly conservative and stringent. This can be especially challenging given that validation and quality assurance activities are often seen as part of a checks and balances system that is almost designed to be confrontational. There are no easy answers here. Every company has a unique culture, but creating one that allows for a cooperative approach can certainly pay dividends.

Articles

Production Trends

Computerized systems can solve some of the data integrity problems with conventional paper-based systems.

Mitigating Data Integrity Risks

	Blow-fill-seal (BFS) provides a sterile solution for aseptic technology by reducing human intervention in the fill/finish process. FDA’s guidance for the industry, 

Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice

, defines BFS as “an automated process by which containers are formed, filled and sealed in a continuous operation” (1). BFS machinery must be designed to “prevent the potential for extraneous contamination,” FDA writes. Bill Hartzel, director, strategic execution, Catalent Pharma Solutions, says BFS can be used with a range of products, from simple solutions to complex biologics. Tim Kram, general manager, Rommelag USA, says, “BFS is best suited for single dose (unit-dose) aseptic and terminally sterilized drug products.” Some drug products suitable for BFS include respiratory, ophthalmic, oral, and injectable drugs.
	
	BFS is internationally accepted as an advanced aseptic liquid processing technology, says Andy Goll, director of sales and marketing at Weiler Engineering. Goll attributes this recognition to the “inherent safety” in BFS processing of drug products, since there is very little, if any, human intervention during BFS processing. While BFS may reduce the likelihood of product contamination, there are several things to consider before selecting BFS technology. Products must be able to withstand momentarily high temperatures and long-term exposure to polymer (2). Factors such as wall thickness, material compatibility, sterility assurance, and product applications are just a few of the components impacting the success of BFS processes. 

 sat down with Hartzel, Kram, and Goll to discuss common considerations and technological advancements in BFS technology.
	
	

 What types of plastic materials can be used with BFS?

 The primary materials used are medical grade polyolefins. For ophthalmic and respiratory products, where squeezability and flexibility are important for administration, low-density polyethylene (LDPE) predominates. For containers intended for storage, high-density polyethylene (HDPE) is more common, and polypropylene (PP) may be used if broader chemical resistance, enhanced barrier properties, or greater thermal stability are required.
	
	

 The main plastic materials used are LDPE, HDPE, and PP.
	
	

 The most common are polyolefins: polyethylene (PE) and PP.

 What are the considerations when choosing a type of plastic for an application? 

 The first check is to see if the product is directly compatible with the plastic resin. Rommelag has standard test kits with sterile 10-mL containers made from various plastics for this purpose. Extractable profiles for the plastics need to be examined for potential incompatibilities with the products. Accelerated and normal stability studies will be performed to find out what leachables are present and what the impacts are. This is the same process that would be performed on a glass vial and its rubber stopper.
	The plastic needs to be able to provide the function the intended use requires. This may be a simple twist-off top or a more complicated feature. The plastic material will also be evaluated for water vapor permeability and gas permeability. Polyolefins have a good water vapor barrier but a gas barrier that is not sufficient for products that are highly sensitive to oxygen or other gases. Products that need additional barrier protection commonly use secondary foil overwraps.

	BFS is an aseptic filling technology, but in the case of injectable products there is a regulatory requirement to perform an overkill terminal sterilization (if the product can withstand the procedure). The most common route for sterilization is steam autoclaving. The standard here is 121 Â°C. PP materials are the most suitable for this application. Injectable products have a regulatory requirement to be inspected for visible particulate. Other product types find it beneficial to have clearer containers. Resins with better clarity are typically preferred over others. Cost is a consideration when considering all the resin options available.

 The main considerations when choosing a plastic are the applications. When filling injectable products, for example, you will most likely need to terminally sterilize the products. If the product is not heat sensitive and can withstand a terminal sterilization cycle of 121 Â°C, then you would want to choose a PP that has the proper barrier characteristics to withstand the high temperature sterilization. The resin characteristics of PP are somewhat similar to that of glass. It is a much harder and more rigid material and often times can be a little more difficult to open depending on the application.

	For most other applications where a high temperature terminal sterilization cycle is not required, LDPE would be the resin of choice. LDPE offers decent oxygen barrier characteristics and is quite successful in most extractable and leachable profiles depending on the product. There are many new LDPE resins which actually have characteristics that allow for a higher terminal sterilization temperature up to 115 Â°C. Most pharmaceutical blow molding grade LDPE resins offer very nice molding capabilities that allow for intricate detail for forming of the main body of the vial, and also opening features that may be more complicated when using PP or HDPE resins.

	HDPE resins are more commonly used for large irrigation and eye-wash bottles where a preservative may be used in the formulation. HDPE has very good oxygen permeation/barrier characteristics to ensure a stable product with a slightly longer shelf life. In applications where a combination of the HDPE resin and a titanium dioxide mixture may be required, HDPE is quite frequently used due to the high extrusion temperatures and homogenous mixing characteristics of the two materials. HDPE is probably the least common resin chosen in most BFS applications.

 When choosing a plastic for a primary container closure; safety, efficacy of the product, and function of the container need to be considered. To check the compatibility, stability studies are required as well as the matching of the physical characteristics or function of the container to deliver the product. For example, if you have eye drops that are applied by squeezing the container to express a drop, you would choose LDPE. Alternatively, if you need to terminally sterilize the product with an autoclave you would choose the higher thermal stability of a PP container. Often, barrier properties are questioned because plastics are semipermeable. Even though there are different rates of permeation depending on plastics (e.g., PP has better barrier properties than LDPE), the use of a foil overwrap is a common practice to provide barrier properties that are similar to glass.

 How long is the product/container at an elevated temperature and are there any concerns related to this?

 The BFS molds have chilled water running through the internal structure of the mold housings. As soon as the mold closes around the parison, the cooling process begins immediately. Additional cooling is applied simply due to the filling process of the liquid drug product. Most product formulations are chilled after batching, which adds an extra level of cooling to the internal surfaces of the vial or bottle. The temperature rise inside the vial is totally dependent on the process and application. Heat transfer studies have been conducted where the product inside the vial could see a temperature rise from 10 Â°C to 12 Â°C. This is dependent on the product temperature entering the vial, internal volume of the vial, and fill volumes inside the vial or bottle.

 This is one of the most frequently asked questions in BFS, especially as more thermally sensitive molecules (i.e., biologics), are evaluating the value of BFS. Catalent has been producing a thermally sensitive biologic using this technology. Additionally, the industry has done a significant amount of work to understand and optimize the control parameters to minimize the heat impact the BFS process can have on the product. This concern is derived from the fact the temperature of the molten plastic as it enters the mold is around 180 Â°C. However, from the data we have generated, the heat is dissipated extremely efficiently allowing the plastic material to cool rapidly in the mold. The main contributing variable is the container design itself, control of the container wall thickness, and fill volumes. Through the implementation of additional temperature controls on the formulation side of the BFS process, such as cooling the bulk solution and insulation, an average product temperature of approximately 23 Â°C can be maintained.

 Methods are available to keep the heat impact upon the product minimal.  Under normal situations, a product can either be filled under room temperature (20 Â°C) or be brought back to room temperature within a few minutes. Most products have heat sensitivity based on a temperature for a certain amount of time, or  do not exceed a temperature. Typically, we are able to modify the BFS system to accommodate these product requirements. In the end, all products need to be tested with the BFS process. Not all products will be compatible.

 What should be considered when optimizing the processing conditions of the BFS equipment?

 The most common considerations when optimizing BFS equipment processing conditions are container function and closure integrity. These two items are related. Wall thickness is a critical process condition for a twist-off top on a unit-dose drug container or a piercing point for a container feeding aseptic liquid to a device. [If the wall is too thick] the torque required to remove the twist-off, or energy to pierce the container, will be too high. [If the wall is too thin], the twist-off may be damaged during secondary packaging or transport and result in a leaking container. For container closure integrity, the most critical point is where the container is to be opened. At that point, the container has been purposely weakened so the closure functions properly. Optimization involves several mechanical systems found on the BFS equipment.

 Product quality and ensuring sterility are the most important considerations and this is always at the forefront of our process design. We need to understand the critical control parameters and ensure the sterile boundary is maintained and the process creates inert containers. As the next step, we evaluate the production efficiency, which is heavily influenced by the formulation, container design, and the packaging requirements of the product. Often times the industry focuses on just the BFS front but secondary packaging requirements are a significant contributor to the overall efficiency and many hidden costs.

 For the BFS process alone, special consideration should be given to process parameter development prior to the validation stage, in the form of an engineering study and proper execution of the process validation. Facility design, the utilization of proper utilities, training of operators, and understanding the BFS process will ensure success to anyone entering the field of BFS technology.

 How have recent technology improvements advanced BFS processing?

 As product applications become more accepted globally, markets requiring more stringent regulatory guidance are demanding process enhancements, which minimize risk for an added level of safety to the patient. The most recent advance for Weiler BFS technology is the introduction of NO2 gas sterilization for the grade A filling zone. In collaboration with Noxilizer, this new technology offers a safe and effective means of a complete 10Â³ endotoxin reduction. Since the grade A filling zone is the critical filling zone, NO2 offers the assurance of a complete decontamination or depyrogenation (customer dependant) cycle prior to the start of a filling campaign.

 In recent years, there have been several innovations, for example the introduction of a filling technology that can reduce particulates, and enhanced temperature controls of the process formulation. But the true innovation has revolved around leveraging the BFS technology to create better primary packages that ultimately assist patients and caregivers. The market is gaining a better understanding of how and where BFS fits into primary packaging design and the processing of aseptic products. The major technology improvements lie in companies taking advantage of the true value of BFS as an advanced aseptic manufacturing process that automates the formation and filling of a primary container closure. The technology can then be leveraged for new markets, and change the way a product is delivered to the patient. It is evident in the creation of new container closures that meet specific patient needs, such as closures with multiple ports, or a flat design that fits within a more compact delivery device. Ultimately, the technology facilitates container designs that can deliver products more effectively.

 Disposable fill systems have been developed that work with BFS technology. This will allow higher-value products to be filled with lower losses than the traditional time-pressure-dosing systems, and reduce the time necessary to set up a machine compared to the standard clean in place/sterilize in place process. Rommelag has also developed a single mold variation for their closed parison rotary technology. This new system adds flexibility while keeping the high aseptic assurance levels offered by the closed parison technology. Other additions include automated vial inspection systems that perform IPC tests that are commonly done by hand, adding repeatability and the ability to give direct feedback to the BFS system. Automated particle inspection for injectable products has also been introduced.


	1. FDA, Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing--Current Good Manufacturing Practice (Rockville, MD, September 2004).
	2. R. Hernandez, 


	When referring to this article, please cite it as C. Hroncich, "Examining Blow-Fill-Seal Technology for Aseptic Processes," 

Troubleshooting

Industry experts discuss common considerations and recent technological advancements in blow-fill-seal technology.

Examining Blow-Fill-Seal Technology for Aseptic Processes

	Software and testing services streamline the traditional trial-and-error blister-pack design process to cut costs for manufacturers of solid-dosage forms and compress time to market. Eliminating expensive reiterations with a more automated design process ensures adequate barrier protection, maximizes shelf life, and eliminates over-packaging.


	Klöckner Pentaplast’s BlisterPro XCEL suite of consulting, design, stability, and prototyping services makes it possible to develop prototype packages in two weeks. Housed at the new kp i.center in Charlottesville, VA, which opened in early 2015, BlisterPro XCEL design services have helped over 20 major pharmaceutical brands bring more than 50 solid-dose products to market more quickly and economically (1).

	Other benefits include reduced materials waste and an uptick in overall productivity. “Speed-to-market, product safety, sustainability and cost control are essential factors in [pharmaceutical manufacturers] growing profitably around the globe,” stated Pierre Ferracci, group senior vice-president, Pharmaceutical Films Division, Klöckner Pentaplast (2).

	“The kp i.center welcomes pharmaceutical developers from around the globe,” said Markus Pischulti, business director pharmaceutical films, Europe, Middle East, Africa (EMEA), noting, “The personalized experience isn’t limited to the facility in Virginia. The kp i.center team regularly exchanges ideas, designs and prototypes with groups in Europe, Asia, and beyond” (1).

	BlisterPro XCEL’s services accelerate pharmaceutical product stability profiling through FreeThink Technology’s ASAPprime shelf-life modeling software and ASAP laboratory studies. FreeThink’s ASAPprime V4.0 integrates information about Klöckner Pentaplast’s Pentapharm film line to expedite selection of the most optimum barrier film for the product (2).  At the kp i.center, modeling and simulation software such as finite element analysis allows designers to explore how a product fits into a proposed package concept and compare design iterations. Designers also use it to examine how different polymers influence performance and how various geometries impact stability and barrier properties. The kp i.center also can perform physical buckling or crush tests to determine how a package performs under load, where deflection occurs, and locate weak points that compromise shelf life. Drop testing validates end-use package performance (3).

	“We have CNC [computerized numerical control] equipment to make tooling and an Uhlmann blister line to run prototypes,” Michael Rashed, senior manager, Global Marketing, Pharmaceutical Films Division, Klöckner Pentaplast, told 

 in an interview at PACK EXPO Las Vegas (September 28–30, 2015). “That way package development doesn’t slow down in-house production lines. We can even model the distribution chain,” he said.


	Package optimization help also is available from Allied Development, which recently added SavvyPack Barrier Assistant to its SavvyPack Analytical Services, a toolbox of integrated value chain, lifecycle, and barrier analysis services. With a database of permeability data for all packaging materials, SavvyPack Barrier Assistant calculates the permeability of any blister structure. Adjusting for thickness, temperature, and humidity allows structures to be optimized without time-consuming and expensive physical testing (4).

	According to Bilcare Research, many major pharmaceutical companies rely on its BilcareOptima service. Available worldwide, it’s been used in Europe, Asia, and North America. In an interview with 

, Ajith Nair, PhD, senior vice-president of Research & Quality at Bilcare Research, said, “Tests that determine the optimum blister film barrier properties for packaging certain pharmaceutical products can take as little as 15 business days. Expedited drug stability tests help overcome the time and resource crunch [that] packaging engineers and formulators of global pharmaceutical companies face when attempting to achieve successful stability studies. The vast majority of packaging-related stability failures can be ascertained by systematically analyzing the product’s physical attributes, as opposed to more stringent, time-consuming chemical testing.”

	Bilcare’s 15-day FastPack process determines a product’s susceptibility to environmental factors such as humidity, temperature, light, and oxygen, through scientifically designed experiments. To ensure accurate results, three batches are tested. Forced degradation testing examines product characteristics such as hygroscopicity, physical degradation, chemical degradation, drug-release properties, hardness and friability, gas liberation, and material/product interaction. Test data identify threshold values and optimum barrier and help optimize material selection.

	Bilcare designs the ideal blister cavity using SolidWorks 3D Software and simulates cavity thinning and moisture permeation through finite element analysis software (5). In addition to blister cavity drawing and permeability data, the FastPack process provides a packaging cost analysis with material specifications and testing methods, plus samples of recommended packaging materials.

	The FastPack process is based on research findings from Bilcare’s BilcareOptima, a scientific packaging development and sensitivity profiling method following quality-by-design principles. Nair said, “It has proved not only sufficient in identifying a product’s optimal packaging materials in terms of cost and barrier protection, but also in yielding a greater than 90% certainty of passing a packaging stability study. For pharmaceutical manufacturers, this means reduced risk of both FDA approval delays due to insufficient package barrier properties and, conversely, wasteful and costly over-packaging.”

	The process enables market launch in optimized packaging, saves development time and cost, provides complete understanding of the product’s sensitivity, simplifies the design of additional packaging structures for specific climatic conditions, identifies stability issues, and documents packaging development (5).


	For cold-formed foil blisters, Constantia Flexibles offers Live Stress Check and Cross-Permeation Simulation (see 

). “Both services are optimal tools to reduce the cost and resources associated with trial-and-error development,” Cora Helberg, marketing and innovation manager, Pharma Division, Constantia Flexibles, said in an interview with 

	The Constantia Live Stress Check tool determines the strain level applied to coldform foil and examines the quality of the forming process. Results are used to optimize the mechanical forming process by showing potential improvements in forming plug designs, plug materials, and process setup (6). Helberg said, “Live Stress Check can be used for different reasons: qualification of new tools; qualification of the coldforming process in the blister line; troubleshooting; basis for blister size optimization; [or] choosing the right material for a given blister shape or production process.”

	To perform the stress check, a pattern of high-resolution dots is printed on the Coldform laminate. The sample is run on the blister machine and inspected with a camera system and special software to identify areas where dots are distorted. An automatically generated, three-dimensional image illustrates the degree of strain on the blister. With this information, adjustments can be made to the process and cavity-shaping tooling (6).

	The Cross-Permeation Simulation determines the level of moisture and oxygen ingress along the seam between the two laminate layers. Such cross-permeation can be controlled by matching the inner layer of the laminate to the barrier needs of the product. For example, for more sensitive products, higher barrier polypropylene can replace a polyvinyl chloride layer.

	Cross-permeation also can be influenced by the blister’s design. Reducing cross-permeation may involve adjusting the sealing area or eliminating blister perforations altogether. Helberg explained, “If the clients know how sensitive their products are, with Cross-Permeation Simulation we are able to give a prediction about the likelihood of a success in the stability test. The method can also be used to identify reasons for shelf-life problems.”


	Another potential aid to blister material optimization is in-house permeation testing. It can be done on equipment from MOCON. Ten times more sensitive than the model it replaces, MOCON’s OX-TRAN Model 2/22 L tester quickly measures oxygen permeation down to 0.005 cc/(m

•day) at precise temperature and relative humidity (RH) conditions. When testing film with unknown characteristics, an auto-test feature determines the optimal parameters and conducts the test to completion.

	Automatic sequential testing supports situations where materials need to be tested at various RH and temperature levels. This feature allows the operator to establish up to 10 different RH and temperature conditions in a single test setup, and then automatically run all tests without further operator input. Changes from wet to dry testing can be done with a click, reducing setup and testing time because operators don’t need to empty the reservoir or wait for the system to dry.

	A gas-saver feature automatically reduces consumption when the system is idle. An install wizard and intuitive touch screen simplify setup and operation. Connectivity options provide remote viewing and control from anywhere in the world. The unit also eliminates several common maintenance expenses and adds safety features to increase component lifetime.

	For companies that prefer to outsource testing, MOCON’s Consulting & Testing Services Group provides standard and advanced permeation testing services. Its global network of labs in Minnesota, Texas, Colorado, Germany, China, Canada, Australia, Switzerland, Poland, India, and the United Kingdom was joined by Life Pack Labs in Vista, CA. A business partnership between MOCON and Life Packaging Technology LLC, Life Pack Labs is dedicated to meeting the packaging design and validation requirements of pharmaceutical and medical-device products (7, 8). Testing is done in accordance with international standards and includes calculation of permeation rates for water vapor, carbon dioxide, and oxygen and measurements for attributes like film thickness, flex strength, and package integrity (8).


	1. Klöckner Pentaplast, “Klöckner Pentaplast at Pharmapack Europe Exploring BlisterPro XCEL Suite of Services,” News Release, Feb. 1, 2016.
	2. Klöckner Pentaplast, “Klöckner Pentaplast Pharmaceutical Films Division Adds Product Shelf Life Modeling to BlisterPro XCEL Package Design and Prototyping Services,” News Release, Sept. 28, 2015.
	3. Klöckner Pentaplast, “Klöckner Pentaplast Design Services,” News Release, Sept. 28, 2015.
	4. Allied Development “SavvyPack, We Are Proud to Introduce a New Feature–the Savvy Pack Barrier Assistant,” Email, Nov. 5, 2015.
	5. Bilcare Research, “

,” accessed Feb. 25, 2016.
	6. Constantia Flexibles, “Constantia Flexibles Introduces Live Stress Check and Cross-Permeation Simulation for Constantia Coldform,” News Release, Jan. 14, 2016.
	7. MOCON, Inc., “Life Pack Labs Open for Business; Offers Package Development, Testing for Pharma, Medical Devices,” News Release, Oct. 13, 2015.
	8. MOCON, Inc., “

:
	When referring to this article, please cite it as H. Forcinio, "Blister Pack Optimization," 

Packaging

Science-based software and testing services expedite the material selection process and ensure blister packs deliver adequate barrier protection for solid-dosage forms without over-packaging.

Equipment and Processing Report-06-15-2016

Mitigating Data Integrity Risks

Examining Blow-Fill-Seal Technology for Aseptic Processes

Blister Pack Optimization